AZD5335，一种靶向叶酸受体α的ADC，在肺腺癌中发挥抗肿瘤作用

AZD5335 is a folate receptor alpha (FRalpha)-targeted antibody-drug conjugate (ADC), incorporating a topoisomerase-1 inhibitor (TOP1i) payload. This ADC is currently being developed as a treatment option for FRalpha-expressing ovarian cancer patients (NCT#05797168-FONTANA). Since FRalpha has been reported to be expressed in lung adenocarcinoma (LUAD), the purpose of these studies was to pre-clinically evaluate AZD5335 efficacy within LUAD. Employing a panel of FRalpha-expressing lung cancer cell lines, we demonstrated target-mediated cytotoxicity of AZD5335 and correlated the in vitro sensitivities with FRalpha expression levels. These studies support ongoing in vivo proof-of-concept studies using cell-derived xenograft models to further define the efficacy and pharmacodynamics of AZD5335. Additional AZD5335 efficacy testing was performed within 9 FRalpha-expressing patient-derived xenograft (PDX) models of LUAD. Five of these 9 models responded to AZD5335 (2.5mg/kg) and exhibited a ≥ 30% reduction in tumor volumes (ORR ≈ 56%); AZD5335-related tumor stasis occurred in three additional models. These pre-clinical efforts indicated FRalpha is an actionable target in LUAD and supported expanding clinical assessment of AZD5335 to LUAD in FONTANA.